BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma

E. Elizabeth Patton, Hans R. Widlund, Jeffery L. Kutok, Kamden R. Kopani, James F. Amatruda, Ryan D. Murphey, Stephane Berghmans, Elizabeth A. Mayhall, David Traver, Christopher D M Fletcher, Jon C. Aster, Scott R. Granter, A. Thomas Look, Charles Lee, David E. Fisher, Leonard I. Zon

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Abstract

Melanoma is the most lethal form of skin cancer, and the incidence and mortality rates are rapidly rising. Epidemiologically, high numbers of nevi (moles) are associated with higher risk of melanoma [1]. The majority of melanomas exhibit activating mutations in the serine/threonine kinase BRAF [2-4]. BRAF mutations may be critical for the initiation of melanoma [5]; however, the direct role of BRAF in nevi and melanoma has not been tested in an animal model. To directly test the role of activated BRAF in nevus and melanoma development, we have generated transgenic zebrafish expressing the most common BRAF mutant form (V600E) under the control of the melanocyte mitfa promoter. Expression of mutant, but not wild-type, BRAF led to dramatic patches of ectopic melanocytes, which we have termed fish (f)-nevi. Remarkably, in p53-deficient fish, activated BRAF induced formation of melanocyte lesions that rapidly developed into invasive melanomas, which resembled human melanomas and could be serially transplanted. These data provide direct evidence that BRAF activation is sufficient for f-nevus formation, that BRAF activation is among the primary events in melanoma development, and that the p53 and BRAF pathways interact genetically to produce melanoma.

Original languageEnglish (US)
Pages (from-to)249-254
Number of pages6
JournalCurrent Biology
Volume15
Issue number3
DOIs
StatePublished - Feb 8 2005

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Nevus
melanoma
Fish
Melanoma
Chemical activation
mutation
Mutation
Protein-Serine-Threonine Kinases
Melanocytes
Skin
Animals
Nevi and Melanomas
melanocytes
Fishes
Skin Neoplasms
Zebrafish
mutants
fish
Danio rerio
lethal genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

Cite this

Patton, E. E., Widlund, H. R., Kutok, J. L., Kopani, K. R., Amatruda, J. F., Murphey, R. D., ... Zon, L. I. (2005). BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Current Biology, 15(3), 249-254. https://doi.org/10.1016/j.cub.2005.01.031

BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. / Patton, E. Elizabeth; Widlund, Hans R.; Kutok, Jeffery L.; Kopani, Kamden R.; Amatruda, James F.; Murphey, Ryan D.; Berghmans, Stephane; Mayhall, Elizabeth A.; Traver, David; Fletcher, Christopher D M; Aster, Jon C.; Granter, Scott R.; Look, A. Thomas; Lee, Charles; Fisher, David E.; Zon, Leonard I.

In: Current Biology, Vol. 15, No. 3, 08.02.2005, p. 249-254.

Research output: Contribution to journalArticle

Patton, EE, Widlund, HR, Kutok, JL, Kopani, KR, Amatruda, JF, Murphey, RD, Berghmans, S, Mayhall, EA, Traver, D, Fletcher, CDM, Aster, JC, Granter, SR, Look, AT, Lee, C, Fisher, DE & Zon, LI 2005, 'BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma', Current Biology, vol. 15, no. 3, pp. 249-254. https://doi.org/10.1016/j.cub.2005.01.031
Patton, E. Elizabeth ; Widlund, Hans R. ; Kutok, Jeffery L. ; Kopani, Kamden R. ; Amatruda, James F. ; Murphey, Ryan D. ; Berghmans, Stephane ; Mayhall, Elizabeth A. ; Traver, David ; Fletcher, Christopher D M ; Aster, Jon C. ; Granter, Scott R. ; Look, A. Thomas ; Lee, Charles ; Fisher, David E. ; Zon, Leonard I. / BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. In: Current Biology. 2005 ; Vol. 15, No. 3. pp. 249-254.
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